tbuckley/cabot-search huggingface dataset:
FAM117B promotes gastric cancer growth and drug resistance by targeting the KEAP1/NRF2 signaling pathway
Authors: Yunjiang Zhou, Yaxin Chen, Yongwei Shi, Leyin Wu, Yingying Tan, Tao Li, Yigang Chen, Jiazeng Xia, Rong Hu
Journal: Journal of Clinical Investigation (2023)

Gastric cancer often shows malignant growth and insensitivity to chemotherapeutic drugs due to the regulation of complex molecular mechanisms, which results in poor prognosis for patients. However, the relevant molecular mechanisms remain unclear. In this study, we reported that family with sequence similarity 117, member B (FAM117B), promoted the growth of gastric cancer cells and reduced the sensitivity of cells to chemotherapeutic drugs. Mechanistically, FAM117B competed with nuclear factor E2–related factor 2 (NRF2) for Kelch-like ECH-associated protein 1 (KEAP1) binding, reduced the ubiquitination degradation of NRF2, and activated the KEAP1/NRF2 signaling pathway. Moreover, FAM117B-induced growth and chemoresistance of gastric cancer cells were NRF2 dependent. We found that FAM117B and NRF2 protein levels were highly expressed in tumor tissues of patients with gastric cancer and their co-overexpression represented an independent factor for poor prognosis. Collectively, our findings reveal that FAM117B is involved in promoting gastric cancer growth and drug resistance, and it could be exploited as a cancer therapeutic target.
Base (HCO3 −/CO3 2−) Transport Properties of SLC4 Proteins: New Insights in Acid-Base Kidney Physiology
Authors: Ira Kurtz, George J. Schwartz
Journal: Journal of the American Society of Nephrology (2023)

H + or base transporters and channels in the mammalian genome play important roles in the maintenance of numerous cellular biochemical and physiologic processes throughout the body. Among the known base transporters, those within the SLC4 and SLC26 gene families are involved in cell, transepithelial, and whole organ function. Whether the functional properties of these transporters involve HCO 3 − , CO 3 2− , or HCO 3 − /CO 3 2− stimulated H + (or OH − ) transport has not received widespread attention in the literature. Accordingly, “bicarbonate” is the term typically used in most textbooks without greater specificity. Moreover, clinicians and physiologists have historically focused on the blood HCO 3 − concentration as the base term in the Henderson–Hasselbalch equation in the analysis of clinical acid-base abnormalities, thus, bicarbonate has been assumed to be the species reabsorbed along the nephron as required to maintain the blood [HCO 3 − ] at approximately 25 mM. However, accumulating data in the literature suggest that carbonate, rather than bicarbonate, is the species absorbed across the proximal tubule basolateral membrane, whereas in the collecting duct, bicarbonate is indeed transported. Various experimental approaches leading to this new concept are herein reviewed.
Striving toward hyperthermia-free analgesia: lessons from loss-of-function mutations of human TRPV1
Authors: Tingting Li, Man-Kyo Chung
Journal: Journal of Clinical Investigation (2023)

Transient receptor potential vanilloid 1 (TRPV1), a receptor for capsaicin and noxious heat, has been one of the most compelling targets for analgesics. However, systemic inhibition of TRPV1 is an impractical approach as a pain killer, since systemic antagonism induces hyperthermia. Two articles in this issue of the JCI report phenotypes from separate, rare missense mutations of human TRPV1. He, Zambelli, and colleagues investigated TRPV1K710N, which showed reduced functionality, while Katz, Zaguri, and co-authors reported on TRPV1N331K, which led to a complete functional knockout. The findings provide insights that will improve our understanding of the endogenous functions of TRPV1 in humans and may facilitate a rational TRPV1-targeting approach to achieve hyperthermia-free analgesia.
Prevalence of Positive COVID-19 Test Results Collected by Digital Self-report in the US and Germany
Authors: Jakob J. Kolb, Jennifer M. Radin, Giorgio Quer, Annika H. Rose, Jay A. Pandit, Marc Wiedermann
Journal: JAMA Network Open (2023)

This cohort study examines traditional surveillance and self-reported COVID-19 test result data collected from independent smartphone app–based studies in the US and Germany.
Single-cell characterization of anti–LAG-3 and anti–PD-1 combination treatment in patients with melanoma
Authors: Jani Huuhtanen, Henna Kasanen, Katriina Peltola, Tapio Lönnberg, Virpi Glumoff, Oscar Brück, Olli Dufva, Karita Peltonen, Johanna Vikkula, Emmi Jokinen, Mette Ilander, Moon Hee Lee, Siru Mäkelä, Marta Nyakas, Bin Li, Micaela Hernberg, Petri Bono, Harri Lähdesmäki, Anna Kreutzman, Satu Mustjoki
Journal: Journal of Clinical Investigation (2023)

BackgroundRelatlimab plus nivolumab (anti-lymphocyte-activation gene 3 plus anti-programmed death 1 [anti-LAG-3+anti-PD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on the immune system is unknown.MethodsWe evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG-3+anti-PD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCRαβ-Seq) combined with other multiomics profiling.ResultsThe highest LAG3 expression was noted in NK cells, Tregs, and CD8+ T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy, resulting in an active phenotype. LAG3+ Tregs expanded, but based on the transcriptome profile, became metabolically silent during the treatment. Last, higher baseline TCR clonality was observed in responding patients, and their expanding CD8+ T cell clones gained a more cytotoxic and NK-like phenotype.ConclusionAnti-LAG-3+anti-PD-1 therapy has profound effects on NK cells and Tregs in addition to CD8+ T cells.Trial registrationClinicalTrials.gov (NCT01968109)FundingCancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland (grant numbers 314442, 311081, 335432, and 335436), and an investigator-initiated research grant from BMS.
Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination
Authors: Hannah Kapell, Luca Fazio, Julia Dyckow, Sophia Schwarz, Andrés Cruz-Herranz, Christina Mayer, Joaquin Campos, Elisa D’Este, Wiebke Möbius, Christian Cordano, Anne-Katrin Pröbstel, Marjan Gharagozloo, Amel Zulji, Venu Narayanan Naik, Anna Delank, Manuela Cerina, Thomas Müntefering, Celia Lerma-Martin, Jana K. Sonner, Jung Hyung Sin, Paul Disse, Nicole Rychlik, Khalida Sabeur, Manideep Chavali, Rajneesh Srivastava, Matthias Heidenreich, Kathryn C. Fitzgerald, Guiscard Seebohm, Christine Stadelmann, Bernhard Hemmer, Michael Platten, Thomas J. Jentsch, Maren Engelhardt, Thomas Budde, Klaus-Armin Nave, Peter A. Calabresi, Manuel A. Friese, Ari J. Green, Claudio Acuna, David H. Rowitch, Sven G. Meuth, Lucas Schirmer
Journal: Journal of Clinical Investigation (2023)

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.
Health Care and Climate Change—Telemedicine’s Role in Environmental Stewardship
Authors: Matthew W. Smith, Amy M. J. O’Shea, Charlie M. Wray
Journal: JAMA Network Open (2023)

Krupal B. Patel, MD, MSc; Brian D. Gonzalez, PhD; Kea Turner, PhD; Amir Alishahi Tabriz, MD; Dana E. Rollison, PhD; Edmondo Robinson, MD; Cristina Naso, MEd; Xuefeng Wang, PhD; Philippe E. Spiess, MD
Endothelial cells LEENE on noncoding RNAs in diabetic vasculopathy
Authors: Aneesh Kallapur, Tamer Sallam
Journal: Journal of Clinical Investigation (2023)

Long noncoding RNAs (lncRNAs) have emerged as key mediators of regulated gene expression in diverse biologic contexts, including cardiovascular disease. In this issue of the JCI, Tang, Luo, and colleagues explored the contributions of lncRNAs in diabetic vasculopathy. The authors identified the lncRNA LEENE as a key mediator of angiogenesis and ischemic response. In a model of diabetic peripheral arterial disease, loss of LEENE led to impaired vascular perfusion, while its overexpression rescued the ischemic defect. The authors used unbiased chromatin affinity assays to decipher LEENE's interactome and mode of action. These findings offer insights as to why patients with diabetes are uniquely susceptible to developing peripheral vascular disease and fill important gaps in our understanding of mechanisms that connect metabolic dysregulation with impaired angiogenesis.
Myeloid-like B cells boost emergency myelopoiesis through IL-10 production during infection
Authors: Masashi Kanayama, Yuta Izumi, Megumi Akiyama, Toyoki Hayashi, Koji Atarashi, Axel Roers, Taku Sato, Toshiaki Ohteki
Journal: The Journal of Experimental Medicine (2023)

Emergency myelopoiesis (EM) is a hematopoietic response against systemic infections that quickly supplies innate immune cells. As lymphopoiesis is strongly suppressed during EM, the role of lymphocytes in that process has not received much attention. Here, we found that myeloid-like B cells (M-B cells), which express myeloid markers, emerge in the bone marrow (BM) after the induction of EM. M-B cells were mainly derived from pre-B cells and preferentially expressed IL-10, which directly stimulates hematopoietic progenitors to enhance their survival and myeloid-biased differentiation. Indeed, lacking IL-10 in B cells, blocking IL-10 in the BM with a neutralizing antibody, and deleting the IL-10 receptor in hematopoietic progenitors significantly suppressed EM, which failed to clear microbes in a cecal ligation and puncture model. Thus, a distinct B cell subset generated during infection plays a pivotal role in boosting EM, which suggests the on-demand reinforcement of EM by adaptive immune cells.
Targeting pleckstrin-2/Akt signaling reduces proliferation in myeloproliferative neoplasm models
Authors: Xu Han, Yang Mei, Rama K. Mishra, Honghao Bi, Atul D. Jain, Gary E. Schiltz, Baobing Zhao, Madina Sukhanova, Pan Wang, Arabela A. Grigorescu, Patricia C. Weber, John J. Piwinski, Miguel A. Prado, Joao A. Paulo, Len Stephens, Karen E. Anderson, Charles S. Abrams, Jing Yang, Peng Ji
Journal: Journal of Clinical Investigation (2023)

Myeloproliferative neoplasms (MPNs) are characterized by the activated JAK2/STAT pathway. Pleckstrin-2 (Plek2) is a downstream target of the JAK2/STAT5 pathway and is overexpressed in patients with MPNs. We previously revealed that Plek2 plays critical roles in the pathogenesis of JAK2-mutated MPNs. The nonessential roles of Plek2 under physiologic conditions make it an ideal target for MPN therapy. Here, we identified first-in-class Plek2 inhibitors through an in silico high-throughput screening approach and cell-based assays, followed by the synthesis of analogs. Plek2-specific small-molecule inhibitors showed potent inhibitory effects on cell proliferation. Mechanistically, Plek2 interacts with and enhances the activity of Akt through the recruitment of downstream effector proteins. The Plek2-signaling complex also includes Hsp72, which protects Akt from degradation. These functions were blocked by Plek2 inhibitors via their direct binding to the Plek2 dishevelled, Egl-10 and pleckstrin (DEP) domain. The role of Plek2 in activating Akt signaling was further confirmed in vivo using a hematopoietic-specific Pten-knockout mouse model. We next tested Plek2 inhibitors alone or in combination with an Akt inhibitor in various MPN mouse models, which showed significant therapeutic efficacies similar to that seen with the genetic depletion of Plek2. The Plek2 inhibitor was also effective in reducing proliferation of CD34-positive cells from MPN patients. Our studies reveal a Plek2/Akt complex that drives cell proliferation and can be targeted by a class of antiproliferative compounds for MPN therapy.
Nonhuman “Authors” and Implications for the Integrity of Scientific Publication and Medical Knowledge
Authors: Annette Flanagin, Kirsten Bibbins-Domingo, Michael Berkwits, Stacy L. Christiansen
Journal: JAMA (2023)

Artificial intelligence (AI) technologies to help authors improve the preparation and quality of their manuscripts and published articles are rapidly increasing in number and sophistication.These include tools to assist with writing, grammar, language, references, statistical analysis, and reporting standards.Editors and publishers also use AI-assisted tools for myriad purposes, including to screen submissions for problems (eg, plagiarism, image manipulation, ethical issues), triage submissions, validate references, edit, and code content for publication in different media and to facilitate postpublication search and discoverability. 1 In November 2022, OpenAI released a new open source, natural language processing tool called ChatGPT. 2,3ChatGPT is an evolution of a chatbot that is designed to simulate human conversation in response to prompts or questions (GPT stands for "generative pretrained transformer").The release has prompted immediate excitement about its many potential uses 4 but also trepidation about potential misuse, such as concerns about using the language model to cheat on homework assignments, write student essays, and take examinations, including medical licensing examinations. 5n January 2023, Nature reported on 2 preprints and 2 articles published in the science and health fields that included ChatGPT as a bylined author. 6Each of these includes an affiliation for ChatGPT, and 1 of the articles includes an email address for the nonhuman "author."According to Nature, that article's inclusion of ChatGPT in the author byline was an "error that will soon be corrected." 6However, these articles and their nonhuman "authors" have already been indexed in PubMed and Google Scholar.Nature has since defined a policy to guide the use of large-scale language models in scientific publication, which prohibits naming of such tools as a "credited author on a research paper" because "attribution of authorship carries with it accountability for the work, and AI tools cannot take such responsibility." 7The policy also advises researchers who use these tools to document this use in the Methods or Acknowledgment sections of manuscripts. 7Other journals 8,9 and organizations 10 are swiftly developing policies that ban inclusion of these nonhuman technologies as "authors" and that range from prohibiting the inclusion of AI-generated text in submitted work 8 to requiring full transparency, responsibility, and accountability for how such tools are used and reported in scholarly publication. 9,10The International Conference on Machine Learning, which issues calls for papers to be reviewed and discussed at its conferences, has also announced a new policy: "Papers that include text generated from a large-scale language model (LLM) such as ChatGPT are
Five plus Three for the Pancreas
Authors: J.-Matthias Löhr, Klaus Pantel
Journal: Clinical Cancer Research (2023)

Summary Preneoplastic high-risk lesions in the pancreas need to be differentiated from low-risk lesions warranting surveillance and eventually surgical intervention. Imaging is used so far; however, certain imaging features are subject to interpretation and hence have their intrinsic flaws. In a recent article, a liquid biopsy with protein and RNA markers demonstrates differentiation based on a blood test. See related article by Zhang et al., p. 1535
Novel sialoglycan linkage for constructing adjuvant-protein conjugate as potent vaccine for COVID-19
Authors: Yu Wen, Ru-Yan Zhang, Jian Wang, Shi-Hao Zhou, Xiao-Qian Peng, Dong Ding, Zhi-Ming Zhang, Hua-Wei Wei, Jun Guo
Journal: Journal of Controlled Release (2023)
PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination
Authors: Xinfang Yu, Wei Li, Haidan Liu, Xu Wang, Cristian Coarfa, Chao Cheng, Xinlian Yu, Zhaoyang Zeng, Ya Cao, Ken H. Young, Yong Li
Journal: Journal of Clinical Investigation (2023)

Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is a transmembrane protein synthesized in the endoplasmic reticulum of tumor cells and transported to the plasma membrane to interact with programmed death 1 (PD-1) expressed on T cell surface. This interaction delivers coinhibitory signals to T cells, thereby suppressing their function and allowing evasion of antitumor immunity. Most companion or complementary diagnostic devices for assessing PD-L1 expression levels in tumor cells used in the clinic or in clinical trials require membranous staining. However, the mechanism driving PD-L1 translocation to the plasma membrane after de novo synthesis is poorly understood. Herein, we showed that mind bomb homolog 2 (MIB2) is required for PD-L1 transportation from the trans-Golgi network (TGN) to the plasma membrane of cancer cells. MIB2 deficiency led to fewer PD-L1 proteins on the tumor cell surface and promoted antitumor immunity in mice. Mechanistically, MIB2 catalyzed nonproteolytic K63-linked ubiquitination of PD-L1, facilitating PD-L1 trafficking through Ras-associated binding 8-mediated (RAB8-mediated) exocytosis from the TGN to the plasma membrane, where it bound PD-1 extrinsically to prevent tumor cell killing by T cells. Our findings demonstrate that nonproteolytic ubiquitination of PD-L1 by MIB2 is required for its transportation to the plasma membrane and tumor cell immune evasion.
Autoantibodies to <scp>Disease‐Related</scp> Proteins in Joints as Novel Biomarkers for the Diagnosis of Rheumatoid Arthritis
Authors: Erik Lönnblom, Monica Leu Agelii, Outi Sareila, Lei Cheng, Bingze Xu, Johan Viljanen, Ingiäld Hafström, Maria L. E. Andersson, Göran Bergström, Anna‐Karin Hultgård Ekwall, Anna Rudin, Alf Kastbom, Christopher Sjöwall, Lennart T. H. Jacobsson, Jan Kihlberg, Inger Gjertsson, Rikard Holmdahl
Journal: Arthritis & Rheumatology (2023)

This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints.We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE).Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98-100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19-26%) of early RA patients seronegative for anti-cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE.A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA.
SLC26A1 is a major determinant of sulfate homeostasis in humans
Authors: Anja Pfau, Karen I. López-Cayuqueo, Nora Scherer, Matthias Wuttke, Annekatrin Wernstedt, Daniela González Fassrainer, Desiree E.C. Smith, Jiddeke M. van de Kamp, Katharina Ziegeler, Kai-Uwe Eckardt, Friedrich C. Luft, Peter S. Aronson, Anna Köttgen, Thomas J. Jentsch, Felix Knauf
Journal: Journal of Clinical Investigation (2023)

Sulfate plays a pivotal role in numerous physiological processes in the human body, including bone and cartilage health. A role of the anion transporter SLC26A1 (Sat1) for sulfate reabsorption in the kidney is supported by the observation of hyposulfatemia and hypersulfaturia in Slc26a1-knockout mice. The impact of SLC26A1 on sulfate homeostasis in humans remains to be defined. By combining clinical genetics, functional expression assays, and population exome analysis, we identify SLC26A1 as a sulfate transporter in humans and experimentally validate several loss-of-function alleles. Whole-exome sequencing from a patient presenting with painful perichondritis, hyposulfatemia, and renal sulfate wasting revealed a homozygous mutation in SLC26A1, which has not been previously described to the best of our knowledge. Whole-exome data analysis of more than 5,000 individuals confirmed that rare, putatively damaging SCL26A1 variants were significantly associated with lower plasma sulfate at the population level. Functional expression assays confirmed a substantial reduction in sulfate transport for the SLC26A1 mutation of our patient, which we consider to be novel, as well as for the additional variants detected in the population study. In conclusion, combined evidence from 3 complementary approaches supports SLC26A1 activity as a major determinant of sulfate homeostasis in humans. In view of recent evidence linking sulfate homeostasis with back pain and intervertebral disc disorder, our study identifies SLC26A1 as a potential target for modulation of musculoskeletal health.